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ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS

1 ANNEX ISUMMARY OF PRODUCT CHARACTERISTICS2 This medicinal PRODUCT is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section for how to report adverse OF THE MEDICINAL PRODUCTEVUSHELD150 mg + 150mg solution for AND QUANTITATIVE COMPOSITIONEach carton contains two vials:Each vial of tixagevimab contains 150 mg of tixagevimabin (100mg/mL).Each vial of cilgavimab contains 150mg of cilgavimab in (100mg/mL).Tixagevimab and cilgavimab are produced in Chinese hamster ovary (CHO) cells by recombinant DNA the full list of excipients, see FORMS olution for injection(injection)Clear to opalescent, colourless to slightly yellow, indicationsPre-exposure prophylaxisEVUSHELDis indicated for thepre-exposure prophylaxis of COVID-19 in adults and adolescents aged 12years and older weighing at least 40kg (see , and ).

listed in Appendix V. 4.9 Overdose ... acid substitutions in the Fc regions, to extend antibody half-life and to reduce antibody effector ... bind to spike with equilibrium dissociation constants of KD= 2.76pM, 13.0pM and 13.7pM, respectively, blocking its interaction with the human ACE2 receptor, resulting in a blockade of virus

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Transcription of ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS

1 1 ANNEX ISUMMARY OF PRODUCT CHARACTERISTICS2 This medicinal PRODUCT is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section for how to report adverse OF THE MEDICINAL PRODUCTEVUSHELD150 mg + 150mg solution for AND QUANTITATIVE COMPOSITIONEach carton contains two vials:Each vial of tixagevimab contains 150 mg of tixagevimabin (100mg/mL).Each vial of cilgavimab contains 150mg of cilgavimab in (100mg/mL).Tixagevimab and cilgavimab are produced in Chinese hamster ovary (CHO) cells by recombinant DNA the full list of excipients, see FORMS olution for injection(injection)Clear to opalescent, colourless to slightly yellow, indicationsPre-exposure prophylaxisEVUSHELDis indicated for thepre-exposure prophylaxis of COVID-19 in adults and adolescents aged 12years and older weighing at least 40kg (see , and ).

2 TreatmentEVUSHELD is indicated for the treatment of adults and adolescents (aged 12years and older weighing at least 40kg) with COVID-19, who do not require supplemental oxygenand who are at increased risk of progressing to severe COVID-19 (see , and ). and method of administrationAdministration should be under conditions where management of severe hypersensitivity reactions, such as anaphylaxis, is possible. Individuals should be observedafter administration according to local medical prophylaxisThe recommended dose in adults and adolescents aged 12 years and older weighing at least 40kg is150 mg of tixagevimab and 150mg of cilgavimab(Table1), administered as two separate sequential intramuscular are no safety and efficacy data available on repeat recommended dose in adults and adolescents aged 12years andolder weighing at least 40kg is 300 mg of tixagevimab and 300 mg of cilgavimab(Table1), administered as two separate sequential intramuscular should be given as soon as possible after a positive viral test for SARS-CoV-2 and within 7days of the onset of symptoms of COVID-19 (see section ).

3 Table1 Recommended doseaEach vial contains an overfill to allow the withdrawal of 150mg ( ).ElderlyNo dose adjustment is required (see ).Renal impairment No dose adjustment is required (see ).Hepatic impairment No dose adjustment is required (see ).Paediatric populationNo dose adjustment is required in adolescents aged 12years and older weighing at least 40kg (see ).The safety and efficacy of EVUSHELDin children under 12 years of age have notyet been data are of administration For intramuscular and cilgavimab must be given as separate sequential intramuscular injections at different injection sites in two different muscles, preferably in the gluteal carton contains two vials: tixagevimab solution for injection (dark grey cap); cilgavimab solution for injection (white cap).For handling instructions of the medicinal PRODUCT before administration, see to the active substances or to any of the excipients listed in + cilgavimabAntibody doseNumber of vials neededaVolume to withdraw from vialPre-exposure prophylaxis150 mg + 150mg(1 EVUSHELD carton)tixagevimab 150 mg1 vial(dark grey cap) mLcilgavimab 150 mg1 vial(white cap) mLTreatment300 mg + 300mg(2 EVUSHELD cartons)tixagevimab 300 mg2 vials (dark grey cap) mLcilgavimab 300 mg2 vials (white cap) warnings and precautions for useTraceabilityIn order to improve the traceability of biological medicinal products, the name andthe batch number of the administered PRODUCT should be clearly including anaphylaxisSerious hypersensitivity reactions, including anaphylaxis, have been observed with monoclonal antibodies.

4 If signs and symptoms of a clinically significant hypersensitivity reaction or anaphylaxis occur, immediately discontinue administration and initiate appropriate medicinal products and/or supportive and/or thrombo-embolic eventsIn the PROVENT study, participantsin the EVUSHELD arm experienced more serious cardiovascular adverse events compared to those in the placebo arm ( versus ), notably coronary events ( myocardial infarction). A smaller imbalance has been observed for serious thrombo-embolic events ( versus ). The majority of subjects had cardiovascular risk factors and/or history of cardiovascular disease that could explain the occurrence of such events. A causal relationship between EVUSHELD and these events has not been risks and benefitsshould be consideredprior to initiating EVUSHELD in individuals at high risk for cardiovascular or thrombo-embolic events.

5 Patients should be advised of signs or symptoms suggestive of cardiovascular event (notably chest pain, dyspnoea, malaise, feeling lightheadedor faint) and to seek immediate medical attention if such symptoms significant bleeding disordersAs with any other intramuscular injections, EVUSHELD should be given with caution to patients with thrombocytopenia or any coagulation resistanceThe clinical trials with EVUSHELD were conducted when Alpha, Beta, Gamma and Delta variantswere predominant. Efficacy of tixagevimab and cilgavimab against some circulating SARS-CoV-2 variants with decreased in-vitro susceptibility is uncertain (see section ).Based on clinical data from PROVENT, the duration of protection following administration of a single EVUSHELD dose (150 mg of tixagevimab and 150 mg of cilgavimab) is estimated to be at least 6 months.

6 Due to the observed decrease in in-vitroneutralisation activity against the Omicron subvariants , ( +R346K), and duration of protection of EVUSHELD for these subvariants is currently not vaccinesPre-exposure prophylaxis with EVUSHELDis not a substitute for vaccination in individuals for whom COVID-19 vaccination is with other medicinal products and other forms of interactionPharmacokinetic interactions No human interaction studies have been not expected to undergo metabolism by hepatic enzymes or renal and cilgavimab are not renally excreted or metabolised by cytochrome P450 (CYP) enzymes; therefore, interactions with medicinal products that are renally excreted or that are substrates, inducers, or inhibitors of CYP enzymes are on pharmacokinetic (PK) modelling, COVID-19 vaccination following EVUSHELD administration had no clinically relevant impact on the clearance of on PK modelling, immunocompromised condition had no clinically relevant impact on the clearance of interactionsNo human interaction studies have been , pregnancy and lactationPregnancyThere are no or limited data from the use of tixagevimab and cilgavimab in pregnant reproductive toxicity studies have not been performed with tixagevimab and cilgavimab(see ).

7 In tissue cross reactivity studies with tixagevimab and cilgavimab using human foetal tissues no binding of clinical concern was immunoglobulin G1 (IgG1) antibodies are known to cross the placentatherefore tixagevimab and cilgavimabhave the potential to be transferred from the mother to the developing foetus. The potential treatment benefit or risk of placental transfer of tixagevimab and cilgavimab to the developing foetus is not be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the is not known whether tixagevimab and cilgavimab are excreted in human milkbut maternal IgG is known to be transferred to milk during the first days after tixagevimab and cilgavimab directly target the spike protein of SARS-CoV-2, and in view of low systemic absorption after oral ingestion of antibodies.

8 Administration of EVUSHELD whilst breast-feeding can be considered when clinically are no data on the effects of tixagevimab and cilgavimab on human on male and female fertility have not been evaluated in animal on ability to drive and use machinesEVUSHELDhas no or negligible influence on the ability to drive and use effectsSummary of the safety profileA total of 4210 adult participants have received 150 mg tixagevimab and 150 mg cilgavimab, via intramuscularinjection, in PhaseIII prophylaxis most common adverse reactions ( 1%) were injectionsite reactions ( ) and hypersensitivity( ).6A total of 452 non-hospitalised adult patients with mild to moderate COVID-19 have received 300mg tixagevimab and 300mg cilgavimab, via intramuscular injection, in a PhaseIII treatment study. The overall safety profile was similar to that reported in participants who received 150mg tixagevimab and 150mg cilgavimab in the prophylaxis studies.

9 The most common adverse reaction ( 1%) was injection site reaction ( ).Tabulated list of adverse reactionsThe adverse reactions in Table2 are listed by MedDRA system organ class and frequency. Frequencies are defined as follows:very common ( 1/10); common ( 1/100 to <1/10); uncommon ( 1/1 000 to <1/100); rare ( 1/10000 to <1/1 000); very rare (<1/10000) and not known (cannot be estimated from available data).Table2 Tabulated list of adverse reactionsMedDRA system organ classAdverse reactionFrequencyaImmune system disordersHypersensitivitybCommon General disorders and administration site conditionsInjection related reactioncUncommonInjury, poisoning and procedural complicationsInjection site reactiondCommonaFrequencies are based on exposure to 150mg tixagevimab and 150mg cilgavimab in the pooled data from the prophylaxis the preferred terms Rash and of events reported under the preferredtermInjection related reactioninclude headache, chills and redness, discomfortor soreness near where the injection was the preferred terms Injection site pain, Injection site erythema, Injection site pruritus, Injection site reaction and Injection site data are available for paediatric patients <18 years old (see and ).

10 Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal PRODUCT is important. It allows continued monitoring of the benefit/risk balance of the medicinal PRODUCT . Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in appendix is no specific treatment for overdose with tixagevimab and cilgavimab. Treatment of overdose should consist of general supportive measures including monitoring of vital signs and observation of the clinical status of the clinical trials,intramuscular doses of up to 300 mg each of tixagevimab and cilgavimab and intravenousdoses of up to 1 500 mg each of tixagevimab and cilgavimab have been administered without dose-limiting propertiesPharmacotherapeutic group: Immune sera and immunoglobulins, antiviral monoclonal antibodies, ATC code: J06BD03 Mechanism of actionTixagevimab and cilgavimab are two recombinant human IgG1 monoclonal antibodies, with amino acid substitutions in the Fc regions, to extend antibody half-life and to reduce antibody effector function and potential risk of antibody-dependent enhancement of disease (see ).